Immunogenicity and tolerability of an investigational formulation of interferon-beta1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis.

Background: RNF (Rebif New Formulation, Merck Serono International S.A., Geneva, Switzerland), a formulation of interferon-beta1a (IFN-beta1a) without human- or animal-derived components, is currently under investigation. It was developed with the aim of maximizing the treatment benefit for patients with multiple sclerosis (MS) by improving injection tolerability and reducing the development of neutralizing antibodies (NAbs).

Objective: This paper reports the results of planned 24- and 48-week interim analyses comparing immunogenicity and tolerability data from an ongoing study of RNF with historical-control data for the currently approved formulation of IFN-beta1a from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study.

Methods: Patients in the 96-week, multicenter, singlearm, Phase IIIb RNF study received 44 microg/0.5 mL SC tiw; patients in the EVIDENCE study received an identical regimen of the currently approved formulation of IFN-beta1a. Criteria for inclusion in the RNF study were age between 18 and 60 years, an Expanded Disability Status Scale (EDSS) score <6.0, and a diagnosis of relapsing MS (McDonald criteria). Criteria for inclusion in the EVIDENCE study were age between 18 and 55 years, an EDSS score of 0 to 5.5, and a diagnosis of clinically definite relapsing-remitting MS (Poser criteria). Patients in both studies were treatment naive. Both studies used the same cytopathic-effect assay for NAbs to assess immunogenicity; patients who had NAb titers >or=20 neutralizing units (NU)/mL were considered NAb+. The primary end point was to compare the proportions of NAb+ patients in the RNF study and the historical data. Comparisons were descriptive and used exact 95% CIs. Safety analyses included 8 prespecified adverse events (AEs) of interest.

Results: Baseline demographic characteristics were well balanced between the RNF (N = 260) and EVIDENCE (N = 339) studies, except that patients in the RNF study were slightly younger (median age, 34.0 vs 39.0 years, respectively), and a few had secondary progressive MS (n = 6) or progressive relapsing MS (n = 1). At week 48, 87.3% of patients in the RNF study remained on treatment. The incidence of the prespecified AEs of interest in the RNF and EVIDENCE studies was as follows: flu-like symptoms (70.8% and 48.1%, respectively), injection-site reactions (29.6% and 83.8%), hepatic disorders (13.1% and 16.8%), cytopenia (9.6% and 11.8%), depression and suicidal ideation (5.8% and 19.8%), skin rashes (5.4% and 12.1%), hypersensitivity reactions (5.4% and 3.2%), and thyroid disorders (2.3% and 5.0%). Overall, the majority (96.9%) of AEs in the RNF study were mild (69.5%) or moderate (27.5%) in severity. The proportions of patients in the RNF and EVIDENCE studies with NAbs at both 24 and 48 weeks were 2.5% (95% CI, 0.9-5.5) and 14.3% (95% CI, 10.7-18.6), respectively; the proportions with NAbs at week 48 only were 13.9% (95% CI, 9.9-18.7) and 24.4% (95% CI, 19.9-29.4). The proportions of NAb+ patients with high NAb titers (>1000 NU/mL) at week 48 were 11.1% in the RNF study and 19.5% in the EVIDENCE study.

Conclusions: The results of these interim analyses suggest that RNF had an improved overall tolerability and safety profile and a lower immunogenic potential compared with the approved IFN-beta1a formulation assessed in the EVIDENCE study. Two-year results from the RNF study are anticipated before the end of 2007.